New beta-agonists, processes for preparing them and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to new beta-agonists of general formula 1:  
                 
 
     wherein the groups R 1  to R 12  have the meanings given in the claims and specification, the isomers thereof, processes for preparing these compounds and their use as pharmaceutical compositions.

[0001] The present invention relates to new beta-agonists of generalformula 1:

[0002] wherein the groups R¹ to R¹² have the meanings given in theclaims and specification, the isomers thereof, processes for preparingthese compounds and their use as pharmaceutical compositions.

BACKGROUND TO THE INVENTION

[0003] The treatment of type II diabetes and obesity is based primarilyon reducing calorie intake and increasing physical activity. Thesemethods are rarely successful in the longer term.

[0004] It is known that beta-3 receptor agonists have a significanteffect on lipolysis, thermogenesis and the serum glucose level in animalmodels of type II diabetes (Arch JR. beta(3)-Adrenoceptor agonists:potential, pitfalls and progress, Eur J Pharmacol. 2002 Apr.12;440(2-3):99-107).

[0005] Compounds which are structurally similar to the compoundsaccording to the invention and their broncholytic, spasmolytic andantiallergic activities were disclosed in DE 2833140, for example.

[0006] The aim of the present invention is to provide selective beta-3agonists which can be used to prepare pharmaceutical compositions forthe treatment of obesity and type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

[0007] Surprisingly it has been found that compounds of general formula(I) wherein the groups R¹ to R¹² are defined as hereinafter areeffective as selective beta-3 agonists. Thus, the compounds according tothe invention may be used to treat diseases connected with thestimulation of beta-3-receptors.

[0008] The present invention therefore relates to compounds of generalformula (I)

[0009] wherein

[0010] R¹, R², R¹⁰, R¹¹ independently of one another denote a groupselected from among hydrogen, halogen, CN, NO₂, and —NHCXNH₂ or

[0011] a group selected from among optionally substituted —COR⁷, —COOR⁷,—CONR⁷R¹³, —OR¹⁴, NR¹³R¹⁵, C₁-C₁₀ -alkyl, C₃-C₈-cycloalkyl, —NR¹⁶CX—R¹⁷, —NR¹⁸CX—OR¹⁹, —NR²⁰SO_(m)R²¹, —SO_(p)NR²²R²³ and —SO_(q)R²⁴,

[0012] m, p, q independently of one another denote 0, 1 or 2,

[0013] n denotes 0, 1, 2 or 3,

[0014] R³ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₀-alkyl, C₆-C₁₀-aryl, heterocyclyl, C₃-C₈-cycloalkyl,—CX—C₁-C₁₀-alkyl and —CX—C₆-C₁₄-aryl,

[0015] R⁴, R⁵ independently of one another denote hydrogen, halogen oroptionally substituted C₁-C₁₀-alkyl, or

[0016] R⁴ and R⁵ together denote a C₃-C₈-alkyl bridge,

[0017] R⁶ denotes a group selected from among the general formulae

[0018] l,k independently of one another denote 1, 2 or 3,

[0019] R²⁵, R²⁶, R²⁷, R²⁸ independently of one another denote a groupselected from among hydrogen, OH, halogen, CN and NO₂, or

[0020] a group selected from among optionally substituted C₁-C₁₀-alkyl,C₆-C₁₈-aryl, heteroaryl, heterocyclyl, —CX—R¹⁷, —OR¹⁴, NR¹³R¹⁵,C₂-C₈-cycloalkyl, —NR²⁰SO_(m)R²¹, —SO_(p)NR²²R²³, —SO_(q)R²⁴,—NR¹⁸CX—R¹⁹, —NR¹⁸CXOR¹⁷, while R²⁵ and R²⁶ cannot simultaneously denotehydrogen,

[0021] R⁸ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₀-alkyl, C₆-C₁₈-aryl, —SO_(q)—C₁-C₁₀-alkyl,—SO_(q)—C₆-C₁₄-aryl, —CX—C₁-C₁₀-alkyl, —CX—C₆-C₁₄-aryl, C₆-C₁₀-aryl,heterocyclyl and C₃-C₈-cycloalkyl

[0022] R⁹ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₀-alkyl, C₆-C₁₄-aryl, heteroaryl, C₃-C₈-cycloalkyl andheterocycloalkyl,

[0023] R¹² denotes hydrogen or a group selected from among optionallysubstituted benzyl, C₁-C₁₂-alkyl and C₆-C₁₄-aryl,

[0024] R⁷, R¹³, R¹⁵, R¹⁶, R¹⁸, R²⁰, R²², R²³ independently of oneanother denote hydrogen, or

[0025] a group selected from among optionally substituted C₁-C₁₀-alkyl,C₆-C₁₄-aryl, heterocyclyl and C₃-C₈-cycloalkyl

[0026] R¹⁴, R¹⁹, R²⁹ independently of one another denote hydrogen or agroup selected from among optionally substituted C₁-C₁₀-alkyl,C₆-C₁₄-aryl, C₃-C₈-cycloalkyl, heteroaryl, heterocyclyl, —CXNR₁₃R₁₅,—CXR₇

[0027] R¹⁷ denotes a group selected from among C₁-C₁₀-alkyl,C₆-C₁₄-aryl, heterocyclyl, heteroaryl and C₃-C₈-cycloalkyl

[0028] R²¹, R²⁴ independently denote hydrogen or OH, or

[0029] a group selected from among optionally substitutedN(C₁-C₁₀-alkyl)₂, N(C₃-C₈-cycloalkyl), C₁-C₁₀-alkyl, C₆-C₁₄-aryl,heterocyclyl, heteroaryl and C₃-C₈-cycloalkyl and

[0030] X denotes O, S or NR²⁹,

[0031] optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, as well asoptionally the pharmacologically acceptable acid addition salts thereof.

[0032] Preferred are compounds wherein

[0033] R¹⁰, R¹¹ independently of one another denote hydrogen or halogen,

[0034] m, p, q denote 0, 1 or 2

[0035] n denotes 0, 1, 2 or 3

[0036] R³ denotes hydrogen or C₁-C₅-alkyl

[0037] R⁴, R⁵ independently of one another denote hydrogen orC₁-C₅-alkyl,

[0038] R⁸ denotes a group selected from among hydrogen, C₁-C₅-alkyl,—SO_(q)—C₁-C₅-alkyl, —SO_(q)—C₆-C₁₄-aryl, phenyl and C₃-C₆-cycloalkyl

[0039] R⁹ denotes hydrogen or C₁-C₁₀-alkyl

[0040] R¹² denotes hydrogen or benzyl

[0041] R¹³, R¹⁵, R¹⁶, R¹⁸ independently of one another denote a groupselected from among hydrogen, C₁-C₅-alkyl, C₃-C₆-cycloalkyl and phenyl

[0042] R¹⁴, R¹⁹ independently of one another denote hydrogen orC₁-C₅-alkyl, and

[0043] R¹⁷ denotes optionally substituted C₁-C₅-alkyl or C₆-C₁₀-aryl.

[0044] Also preferred are compounds wherein

[0045] R¹⁰, R¹¹ denotes hydrogen

[0046] m, p, q denote 0, 1 or 2

[0047] n denotes 0, 1, 2 or 3

[0048] R³ denotes hydrogen

[0049] R⁴, R⁵ independently of one another denote hydrogen or methyl,

[0050] R⁸ denotes hydrogen, —SO_(q)—C₆-C₁₄-aryl or —SO₂—C₁-C₅-alkyl

[0051] R⁹ denotes hydrogen

[0052] R¹² denotes hydrogen or benzyl,

[0053] R¹³, R¹⁵, R¹⁶, R¹⁸ independently of one another denote a groupselected from among hydrogen, C₁-C₁₅-alkyl and phenyl,

[0054] R¹⁴, R¹⁹ independently of one another denote hydrogen orC₁-C₅-alkyl, and

[0055] R¹⁷ denotes C₁-C₅-alkyl or C₆-C₁₄-aryl.

[0056] Particularly preferred are compounds wherein

[0057] R¹ denotes a group selected from among hydrogen, NO₂, NH₂,—NHCX—R¹⁷ and —NHSO₂R²¹.

[0058] R² denotes hydrogen or halogen

[0059] n denotes 2,

[0060] R³ denotes hydrogen

[0061] R⁴, R⁵ denote hydrogen or methyl

[0062] R⁶ denotes a group selected from among the general formulae

[0063] l,k denotes 1

[0064] R²⁶, R²⁷ denotes hydrogen,

[0065] R⁸ denotes hydrogen or —SO₂CH₃,

[0066] R⁹ denotes hydrogen,

[0067] R¹⁰, R¹¹ denote hydrogen, and

[0068] R¹² denotes hydrogen or benzyl.

[0069] Also particularly preferred are compounds wherein

[0070] R⁶ denotes a group selected from among the general formulae

[0071] Particularly preferred are compounds wherein

[0072] R⁶ denotes an optionally substituted group of formula (j)

[0073] The invention further relates to compounds of formula (I) for useas pharmaceutical compositions.

[0074] The invention further relates to compounds of formula (I) for useas pharmaceutical compositions with a selective beta-3-agonisticactivity.

[0075] The invention further relates to the use of a compound of formula(I) for preparing a pharmaceutical composition for the treatment and/orprevention of diseases connected with the stimulation ofbeta-3-receptors.

[0076] The invention further relates to a method for the treatmentand/or prevention of diseases connected with the stimulation ofbeta-3-receptors, in which a patient is given an effective amount of acompound of formula I.

[0077] Of particular importance according to the invention is apharmaceutical composition containing as active substance one or morecompounds of general formula (I) or the physiologically acceptable saltsthereof, optionally combined with conventional excipients and/orcarriers.

[0078] Also of particular importance is a pharmaceutical compositioncontaining as active substance one or more compounds of general formula(I) according to one of claims 1 to 6 or the physiologically acceptablesalts thereof and one or more active substances selected from amongantidiabetics, inhibitors of protein tyrosinephosphatase 1, substanceswhich influence deregulated glucose production in the liver, lipidlowering agents, cholesterol absorption inhibitors, HDL-raisingcompounds, active substances for the treatment of obesity and modulatorsor stimulators of the adrenergic receptor via alpha 1 and alpha 2 aswell as beta 1, beta 2 and beta 3 receptors.

[0079] The invention further relates to a process for preparing acompound of general formula (I),

[0080] wherein

[0081] R¹-R²⁸ and X may be as hereinbefore defined,

[0082] wherein a compound of general formula (II)

[0083] where

[0084] R⁴ and R⁵ may be as hereinbefore defined,

[0085] is converted by means of a chlorinating agent into a compound offormula (III)

[0086] the compound of formula (III), optionally provided with an aminoprotective group, is reacted with an optionally substituted compoundselected from among the general formulae (IVa) to (IVi)

[0087] wherein

[0088] k, l, R²⁷ and R²⁸ are as hereinbefore defined,

[0089] and the product of formula (V)

[0090] wherein n, R⁴, R⁵, R⁶ and R⁸ are as hereinbefore defined,

[0091] is reacted with a compound of formula (VIa) to (VIc)

[0092] wherein R¹, R², R⁹ and R¹⁰ to R¹² are as hereinbefore defined.

[0093] The term alkyl groups, including alkyl groups which are a part ofother groups, denotes branched and unbranched alkyl groups with 1 to 10carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as,for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl and decyl. Unless otherwise stated, the above-mentioned termspropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include allthe possible isomeric forms. For example, the term propyl includes thetwo isomeric groups n-propyl and iso-propyl, the term butyl includesn-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includesiso-pentyl, neopentyl, etc.

[0094] In the above-mentioned alkyl groups one or more hydrogen atomsmay optionally be replaced by other groups. For example these alkylgroups may be substituted by the halogen atoms fluorine, chlorine,bromine or iodine. Preferably the substituents are fluorine or chlorine,most preferably chlorine. All the hydrogen atoms of the alkyl group mayoptionally also be replaced.

[0095] Similarly, in the above-mentioned alkyl groups, unless otherwisestated, one or more hydrogen atoms may optionally be replaced, forexample, by an optionally substituted group selected from among OH, NO₂,CN, —O—C₁-C₅-alkyl, preferably —O-methyl or —O-ethyl, O—C₆-C₁₄-aryl,preferably O-phenyl, O-heteroaryl, preferably O-thienyl, O-thiazolyl,O-imidazolyl, O-pyridyl, O-pyrimidyl or O-pyrazinyl, saturated orunsaturated O-heterocycloalkyl, preferably O-pyrazolyl, O-pyrrolidinyl,O-piperidinyl, O-piperazinyl or O-tetrahydro-oxazinyl, C₆-C₁₄-aryl,preferably phenyl, heteroaryl, preferably thienyl, thiazolyl,imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturatedheterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl or tetrahydro-oxazinyl, an amine group, preferablymethylamine, benzylamine, phenylamine or heteroarylamine, saturated orunsaturated bicyclic ring systems, preferably benzimidazolyl andC₃-C₈-cycloalkyl, preferably cyclohexyl or cyclopropyl.

[0096] The term aryl denotes an aromatic ring system with 6 to 18 carbonatoms, preferably 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms,most preferably phenyl, which, unless otherwise stated, may carry one ormore of the following substituents, for example: OH, NO₂, CN, —OCHF₂,—OCF₃, —NH₂, halogen, for example fluorine, chlorine, bromine or iodine,preferably fluorine or chlorine, particularly preferably fluorine,C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl, mostpreferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably —O-methyl or—O-ethyl, —COOH or —CONH₂.

[0097] Examples of heteroaryl groups are 5-10-membered mono- or bicyclicheteroaryl rings wherein up to three C atoms may be replaced by one ormore heteroatoms selected from among oxygen, nitrogen or sulphur, forexample furan, thiophene, pyrrole, pyrazole, imidazole, triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine,oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, while each of theabove-mentioned heterocycles may optionally also be annellated to abenzene ring, preferably benzimidazole, and unless otherwise specifiedthese heterocycles may for example carry one or more of the followingsubstituents: OH, NO₂, CN, —NH₂, halogen, preferably fluorine orchlorine, C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl,particularly preferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably—O-methyl or —O-ethyl, —COOH, —COOCH₃, —CONH₂, —SO-alkyl, —SO₂-alkyl,—SO₂H, —SO₃-alkyl or optionally substituted phenyl.

[0098] Examples of cycloalkyl groups are saturated or unsaturatedcycloalkyl groups with 3 to 8 carbon atoms for example cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl orcyclohexyl, while each of the above-mentioned cycloalkyl groups mayoptionally also carry one or more substituents or be annellated to abenzene ring.

[0099] Unless otherwise stated in the definitions, examples ofheterocycloalkyl groups include 5-, 6- or 7-membered, saturated orunsaturated heterocycles which may contain nitrogen, oxygen or sulphuras heteroatoms, for example tetrahydrofuran, tetrahydrofuranone,γ-butyrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane,dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine,pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole,piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,tetrazine, morpholine, thiomorpholine, diazepan, oxazine,tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, while theheterocyclic group may optionally be substituted.

[0100] The halogen is generally fluorine, chlorine, bromine or iodine,preferably chlorine or fluorine, particularly preferably fluorine.

[0101] The compounds according to the invention may be present in theform of the individual optical isomers, mixtures of the individualenantiomers, diastereomers or racemates, in the form of the tautomersand also in the form of the free bases or the corresponding acidaddition salts with pharmacologically acceptable acids—such as forexample acid addition salts with hydrohalic acids, for examplehydrochloric or hydrobromic acid, or organic acids, such as for exampleoxalic, fumaric, diglycolic, formic, malic, benzoic, benzenesulphonic,camphorsulphonic, acetic, ethanesulphonic, glutamic, maleic, mandelic,lactic, phosphoric, nitric, sulphuric, succinic, para-toluenesulphonic,trifluoroacetic, tartaric, citric or methanesulphonic acid.

[0102] The substituent R¹ may denote a group selected from amonghydrogen, halogen, preferably fluorine or chlorine, CN, NO₂, and—NHCXNH₂, preferably NHCONH₂ or

[0103] a group selected from among optionally substituted —COR⁷, —COOR⁷,—CONR⁷R³, —OR¹⁴, preferably OH, NR¹³R¹⁵, C₁-C₁₀-alkyl, C₃-C₈-cycloalkyl,—NR¹⁶CX—R¹⁷, —NR¹⁸CX—OR¹⁹, —NR²⁰SO_(m)R²¹, —SO_(p)NR²²R²³, preferably—SO₂NHR²³, and —SO_(q)R².

[0104] In particular the substituent R¹ denotes —NR²⁰SO_(m)R²¹,preferably —NHSO_(m)R²¹.

[0105] The substituent R² may denote a group selected from amonghydrogen, halogen, preferably fluorine or chlorine, CN, NO₂, and—NHCXNH₂, preferably NHCONH₂ or

[0106] a group selected from among optionally substituted —COR⁷, —COOR⁷,—CONR⁷R¹³, —OR¹⁴, preferably OH, NR¹³R¹⁵, C₁-C₁₀-alkyl,C₃-C₈-cycloalkyl, —NR¹⁶CX—R¹⁷, —NR¹⁸CX—OR¹⁹, —NR²⁰SO_(m)R²¹,—SO_(p)NR²²R²³, preferably —SO₂NHR²³ and —SO_(q)R²³. In particular thesubstituent R² denotes hydrogen or fluorine.

[0107] The substituents R¹⁰ and R¹¹ may be identical or different anddenote a group selected from among hydrogen, halogen, preferablyfluorine or chlorine, CN, NO₂, and —NHCXNH₂, preferably NHCONH₂ or

[0108] a group selected from among optionally substituted —COR⁷, —COOR⁷,—CONR⁷R¹³, —OR¹⁴, preferably OH, NR¹³R¹⁵, C₁-C₁₀-alkyl,C₃-C₈-cycloalkyl, —NR¹⁶CX—R¹⁷, —NR¹⁸CX—OR¹⁹, —NR²⁰SO_(m)R²¹,—SO_(p)NR²²R²³preferably —SO₂NHR²³ and —SO_(q)R². Particularlypreferably, the substituents R¹⁰ and R¹¹ denote hydrogen.

[0109] The variables m, p and q may represent 0, 1 or 2, preferably 2.

[0110] The variable n may represent 0, 1, 2 or 3, preferably 2.

[0111] The substituent R³ may denote hydrogen or a group selected fromamong optionally substituted C₁-C₁₀-alkyl, C₆-C₁₀-aryl, heterocyclyl andC₃-C₈-cycloalkyl, —CX—C₁-C₁₀-alkyl, —CX—C₆-C₁₄-aryl.

[0112] Preferably the substituent R³ denotes hydrogen.

[0113] The substituents R⁴ and R⁵ may be identical or different anddenote hydrogen, halogen or optionally substituted C₁-C₁₀-alkyl,preferably hydrogen or C₁-C₁₀-alkyl, particularly preferably hydrogen ormethyl, or

[0114] R⁴ and R⁵ together may form a C₃-C₈-alkyl bridge, preferably acyclohexyl, cyclopentyl or cyclopropyl bridge.

[0115] The substituent R⁶ may denote a group selected from among thegeneral formulae

[0116] while

[0117] the variables l and k independently of one another denote 1, 2 or3, preferably 1.

[0118] Particularly preferably, R⁶ denotes

[0119] More preferably, R⁶ denotes

[0120] The substituents R²⁵, R²⁶, R²⁷, R²⁸ may be identical or differentand denote a group selected from among hydrogen, OH, halogen, CN andNO₂, or

[0121] a group selected from among optionally substituted C₁-C₁₀-alkyl,C₆-C₁₈-aryl, preferably phenyl, heteroaryl, preferably pyridyl,heterocyclyl, —CX—R¹⁷, —OR¹⁴, NR¹³R¹⁵, C₂-C₈-cycloalkyl, —NR²⁰SO_(m)R²¹,—SO_(p)NR²²R²³, —SO_(q)R²⁴, —NR¹⁸CX—R¹⁹, —NR¹⁸CXOR¹⁷, while R²⁵ and R²⁶cannot simultaneously denote hydrogen.

[0122] The substituent R⁸ may represent hydrogen or a group selectedfrom among optionally substituted C₁-C₁₀-alkyl, C₆-C₁₈-aryl,—SO_(q)—C₁-C₁₀-alkyl, —SO_(q)—C₆-C₁₄-aryl, —CX—C₁-C₁₀-alkyl,—CX—C₆-C₁₄-aryl, C₆-C₁₀-aryl, heterocyclyl and C₃-C₈-cycloalkyl,preferably hydrogen or —SO₂CH₃.

[0123] The substituent R⁹ may represent hydrogen or a group selectedfrom among optionally substituted C₁-C₁₀-alkyl, C₆-C₁₄-aryl, heteroaryl,C₃-C₈-cycloalkyl and heterocycloalkyl, preferably hydrogen.

[0124] The substituent R¹² may represent hydrogen or a group selectedfrom among optionally substituted benzyl, C₁-C₁₂-alkyl and C₆-C₁₄-aryl,CX—C₁-C₁₂-alkyl and CX—C₆-C₁₄-aryl, preferably hydrogen.

[0125] The substituents R⁷, R¹³, R¹⁵, R¹⁶, R¹⁸, R²⁰, R²², R²³ and R²⁴may be identical or different and represent hydrogen, or

[0126] a group selected from among optionally substituted C₁-C₁₀-alkyl,C₆-C₁₄-aryl, heterocyclyl and C₃-C₈-cycloalkyl.

[0127] Particularly preferably, the substituent R²⁰ denotes methyl,ethyl or isopropyl.

[0128] The substituents R¹⁴, R¹⁹ and R²⁹ may be identical or differentand denote hydrogen or a group selected from among optionallysubstituted C₁-C₁₀-alkyl, preferably methyl or difluoromethyl,C₆-C₁₄-aryl, C₃-C₈-cycloalkyl, heteroaryl, heterocyclyl, —CXNR₁₃R₁₅,

[0129] particularly preferably the substituent R¹⁴ denotes methyl ordifluoromethyl.

[0130] The substituent R¹⁷ may denote a group selected from amongC₁-C₁₀-alkyl, preferably methyl or ethyl, C₆-C₁₄-aryl, heterocyclyl,heteroaryl and C₃-C₈-cycloalkyl.

[0131] The substituent R²¹ may represent hydrogen or OH, or

[0132] a group selected from among optionally substitutedN(C₁-C₁₀-alkyl)₂, N(C₃-C₈-cycloalkyl), C₁-C₁₀-alkyl, C₆-C₁₄-aryl,heterocyclyl, heteroaryl and C₃-C₈-cycloalkyl.

[0133] X may represent O, S or NR²⁹, preferably O.

[0134] The compounds according to the invention may be prepared by themethods of synthesis described hereinafter, where formulae (I) to (IV)and the substituents of general formulae R¹ to R¹² have theabove-mentioned meanings. These processes are intended as anillustration of the invention without restricting it to their content.

[0135] Synthesis of 3-chloro-propylamine-hydrochloride (Compound III):

[0136] A compound of formula (II) is converted into a compound offormula (III) using a chlorinating agent.

[0137] Compound (II) may be prepared by methods known from theliterature, for example DE 2200108 (Pander, Hans J.3-amino-3-methyl-1-butanol, Ger. Offen. (1973), 6 pp.).

[0138] About 0.5 mol of compound (II) are dissolved or suspended inabout 100 to 300 ml of a solvent, preferably in methylenechloride/dimethylformamide (50:1), pyridine, carbon tetrachloride,chloroform or dichloromethane. At about −3 to 5° C. , preferably at 0°C., 0.4 to 0.9 mol. preferably 0.6 mol of a chlorinating agent,preferably thionyl chloride, N-chlorosuccinimide, para-toluenesulphonicacid chloride, methanesulphonic acid chloride/lithium chloride orzinc(II)chloride/triphenylphosphine/diethyidiazodicarboxylate, mostpreferably thionyl chloride, are added dropwise to the mixture, withstirring. The solvent is removed, the residue is washed withacetonitrile for example and dried.

[0139] Synthesis of the Dichlorobenzylidenamine of Compound (III):

[0140] The base is liberated from about 80-90, preferably 84.0 mmol of3-chloro-1,1-dimethylpropylamine-hydrochloride by known methods. Thefree base is dissolved in about 50 mL of a solvent, preferably toluene,diethylethylether, tetrahydrofuran, dimethylsulphoxide,dimethylformamide or methylene chloride and about 60 to 100 mmol,preferably 80.0 mmol of 2,6-dichlorobenzaldehyde are added at ambienttemperature, with stirring. The reaction mixture is stirred for 5 to 20h, preferably for 15 h at ambient temperature, dried again and thesolvent is removed. The corresponding dichlorobenzylidenamine ofcompound (III) is obtained.

[0141] Synthesis of the Dichlorobenzylidenamine of Compound (V):

[0142] 30 to 45 mmol, preferably 39.0 mmol of a base, for example sodiumhydride, are added to a solution of 25 to 40 mmol, preferably 33.0 mmol,of one of the compounds (IVa) to (IVi) in about 25 to 100 ml, preferably50 mL of a solvent, for example tetrahydrofuran, dimethylsulphoxide,dimethylformamide or N-methylpyrrolidine, preferably1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone at 5 to 15° C.,preferably about 10° C., with stirring. After the addition has ended thereaction mixture is stirred for 1 h at ambient temperature and then 35to 45 mmol, preferably 39.0 mmol of the dichlorobenzylidenamine ofcompound (III), dissolved in a solvent, preferably about 50 mL of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, as well as 2 to 4mmol, preferably about 3.3 mmol of tetrabutylammonium iodide are added.The reaction mixture is stirred for about 5 to 20 hours, preferably 18 hat ambient temperature, then about 4 h at 80° and then poured into about200 mL ice water/ethyl acetate (1:1). The phases are separated and theaqueous phase is extracted with ethyl acetate. The combined organicphases are dried and the solvent is eliminated. The residue is combinedwith hydrochloric acid and stirred for about 1 h at about 100° C. Thereaction mixture is cooled to about 0° C., combined with ethyl acetateand the pH is adjusted to 10, for example, with sodium hydroxidesolution. The phases are separated and the aqueous phase is extractedwith ethyl acetate. The combined organic phases are dried and thesolvent is eliminated using the rotary evaporator. The residue ispurified by chromatography, for example. About 430 mmol of compound (V)are obtained.

[0143] Synthesis of Compound (I):

[0144] The base is liberated from about 3 mmol of compound (V) usingknown methods. The free base is dissolved in methylene chloride and atambient temperature about 2.6 mmol of a compound of formula (VI a-c) andabout 2.6 mmol of ytterbium(III)trifluoromethanesulphonate are added,with stirring. The reaction mixture is stirred for about 3 days atambient temperature and then water is added. The phases are separatedand the aqueous phase is extracted with methylene chloride, for example.The combined organic phases are dried and the solvent is eliminated. Theresidue is purified by chromatography, for example.

[0145] About 0.1 mmol platinum(IV)oxide are added to a solution of about0.3 mmol of the purified residue in for example about 10 mLtetrahydrofuran/toluene (1:1). The reaction mixture is shaken in anautoclave under a hydrogen pressure of about 10 psi at ambienttemperature for about 5 to 20 h, preferably 16 h. The platinum(IV)oxideis filtered off and the filtrate is freed from solvent. Compound I isthus obtained.

[0146] The new compounds of general formula (I) may be synthesisedanalogously to the following examples of synthesis. These Examples areintended only as examples of procedures to illustrate the invention inmore detail without restricting it to their contents.

EXAMPLE 1

[0147] a) Synthesis of 3-chloro-1,1-dimethylpropylamine-hydrochloride

[0148] 48.7 mL (668 mmol) of thionyl chloride were slowly added dropwiseto a solution of 53.0 g (514 mmol) of 3-amino-3-methyl-butanol in 255 mLmethylene chloride/dimethylformamide (50:1) at 0° C. with vigorousstirring. After the addition was complete the reaction mixture wasrefluxed for 1 h and then stirred for 16 h at ambient temperature. Thesolvent was removed and the residue was combined with 50 mL acetonitrilewith stirring. The solid was filtered off and dried at 45° C. for 18 h.67.9 g (430 mmol, 84%) of 3-chloro-1,1-dimethylpropylamine-hydrochloridewere obtained as a colourless solid.

[0149] MS: (M+H)=122/124 (Cl)

[0150] b) Synthesis of(3-chloro-1,1-dimethylpropyl)-(2,6-dichlorobenzylidene)-amine

[0151] 13.3 g (84.0 mmol) of3-chloro-1,1-dimethylpropylamine-hydrochloride were added to 84.0 mLsodium hydroxide solution (1 M) at 0° C. with vigorous stirring. Thereaction mixture was stirred for 30 min at 0° C. and then combined with50 mL methylene chloride. The phases were separated and the aqueousphase was twice extracted with 35 mL methylene chloride. The combinedorganic phases were dried over magnesium sulphate and at ambienttemperature combined with 14.2 g (81.0 mmol) of 2,6-dichlorobenzaldehydewith stirring. The reaction mixture was stirred for 18 h at ambienttemperature, dried again with magnesium sulphate and the solvent wasremoved. 22.3 g (80.0 mmol, 99%)(3-chloro-1,1-dimethylpropyl)-(2,6-dichlorobenzylidene)-amine wereobtained as a yellowish oil.

[0152] MS: (M+H)=278/280/282 (Cl3)

[0153] c) Synthesis of1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamine

[0154] 1.60 g (50% in oil, 39.0 mmol) sodium hydride were slowly addedto a solution of 4.80 g (33.0 mmol) of 4-phenylimidazole in 50 mL of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone at 10° C. with vigorousstirring. After the addition was complete the reaction mixture wasstirred for 1 h at ambient temperature, and then 10.9 g (39.0 mmol) of(3-chloro-1,1-dimethylpropyl)-(2,6-dichlorobenzylidene)-amine dissolvedin 50 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone and also1.20 g (3.33 mmol) of tetrabutylammonium iodide were added. The reactionmixture was stirred for 18 h at ambient temperature, stirred for 4 h at80° and then poured into 200 mL of ice water/ethyl acetate (1:1). Thephases were separated and the aqueous phase was extracted three timeswith 50 mL of ethyl acetate. The combined organic phases were dried overmagnesium sulphate and the solvent was removed. The residue was combinedwith 11 mL hydrochloric acid (3.5 M) and stirred for 1 h at 100° C. Thereaction mixture was cooled to 0° C., combined with 50 ml of ethylacetate and the pH was adjusted to 10 with sodium hydroxide solution(1M). The phases were separated and the aqueous phase was extractedthree times with 50 mL ethyl acetate. The combined organic phases weredried over magnesium sulphate and the solvent was removed. The residuewas purified by flash column chromatography [methylenechloride/methanol/ammonia (90:10:1)]. 67.9 g (430 mmol, 83%)3-chloro-1,1-dimethylpropylamine-hydrochloride were obtained as acolourless solid.

[0155] MS: (M+H)=230

[0156] R_(f): 0.30 [methylene chloride/methanol/ammonia (90:10:1)]

[0157] d) Synthesis of(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol

[0158] 0.90 g (3.1 mmol) of3-chloro-1,1-dimethylpropylamine-hydrochloride were added to 10 mLsodium hydroxide solution (1 M) at 0° C. with vigorous stirring. Thereaction mixture was stirred for 30 min at 0° C. and then combined with20 mL methylene chloride. The phases were separated and the aqueousphase was extracted twice with 20 mL of methylene chloride. The combinedorganic phases were dried over magnesium sulphate and the solvent waseliminated using a rotary evaporator. The residue was dissolved in 5.0mL of methylene chloride and combined at ambient temperature with 0.70 g(2.6 mmol) (R)-2-(4-benzyloxy-3-nitrophenyl)-oxirane and 0.20 g (0.26mmol) ytterbium (III) trifluoromethanesulphonate, with vigorousstirring. The reaction mixture was stirred for 3 d at ambienttemperature and then combined with 30 mL water/methylene chloride (1:1).The phases were separated and the aqueous phase was extracted twice with20 mL methylene chloride. The combined organic phases were dried overmagnesium sulphate and the solvent was eliminated using a rotaryevaporator. The residue was purified by flash column chromatography[methylene chloride/methanol/ammonia (90:10:1)]. 0.40 g (0.86 mmol, 33%)of(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolwas obtained as a yellowish solid.

[0159] MS: (M+H)=501, (M−H)=499

[0160] R_(f): 0.27 [methylene chloride/methanol/ammonia (90:10:1)]

[0161] e) Synthesis of(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol

[0162] 0.025 g (0.11 mmol) platinum(IV)oxide were added to a solution of0.15 g (0.28 mmol)(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolin 10 mL tetrahydrofuran/toluene (1:1). The reaction mixture was shakenin an autoclave under a hydrogen pressure of 10 psi at ambienttemperature for 16 h. The hydrogen pressure was released, theplatinum(IV)oxide was filtered off and the filtrate was freed fromsolvent. 0.14 g (0.28 mmol, 99%)(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolwere obtained as a brown oil.

[0163] MS: (M+H)=471, (M−H)=469

[0164] R_(f): 0.26 [ethyl acetate/methanol/ammonia (90:10:1)]

[0165] f) Synthesis of(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamide

[0166] 0.10 mL (41 mmol) benzenesulphonic acid chloride were slowlyadded at 0° C. to a solution of 0.20 g (41 mmol)(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolin 5 mL pyridine with vigorous stirring. After the addition was completethe reaction mixture was stirred for 4 h at 0° C. and then poured into40 mL ice water/ethyl acetate (1:1). The phases were separated and theaqueous phase was extracted three times with 20 mL of ethyl acetate. Thecombined organic phases were dried over magnesium sulphate and thesolvent was removed using the rotary evaporator. 0.14 g (0.28 mmol, 99%)(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamidewas obtained as a white solid.

[0167] MS: (M+H)=611, (M−H)=609

[0168] R_(f): 0.36 [methylene chloride/methanol/ammonia (90:10:1)]

[0169] g) Synthesis of(R)-N-(5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-2-hydroxy-phenyl)-benzenesulphonamide

[0170] 0.10 g palladium (5% on activated charcoal) were added to asolution of 0.30 g (0.41 mmol)(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}phenyl)-benzenesulphonamidein 15 mL ethanol. The reaction mixture was shaken in an autoclave undera hydrogen pressure of 20 psi at ambient temperature for 3 h. Thehydrogen pressure was released, the palladium was filtered off and thefiltrate was freed from solvent using the rotary evaporator. The residuewas purified by flash column chromatography [methylenechloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%)(R)-N-(5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-2-hydroxy-phenyl)-benzenesulphonamidewas obtained as a colourless solid.

[0171] MS: (M+H)=521, (M−H)=519

[0172] R_(f): 0.33 [methylene chloride/methanol/ammonia (90:10:1)

EXAMPLE 5

[0173] a) Enantiomerically Pure Synthesis of(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol

[0174] 0.90 g (3.1 mmol) of3-chloro-1,1-dimethylpropylamine-hydrochloride were added to 10 mLsodium hydroxide solution (1 M) at 0° C. with vigorous stirring. Thereaction mixture was stirred for 30 min at 0° C. and then combined with20 mL methylene chloride. The phases were separated and the aqueousphase was extracted twice with 20 mL methylene chloride. The combinedorganic phases were dried over magnesium sulphate and the solvent waseliminated. The residue was dissolved in 5.0 mL methylene chloride andat ambient temperature combined with 0.70 g (2.6 mmol)(R)-2-(4-benzyloxy-3-nitrophenyl)-oxirane and 0.20 g (0.26 mmol)ytterbium (III) trifluoromethanesulphonate with stirring. The reactionmixture was stirred for 3 d at ambient temperature and then combinedwith 30 mL water/methylene chloride (1:1). The phases were separated andthe aqueous phase was extracted twice with 20 mL methylene chloride. Thecombined organic phases were dried over magnesium sulphate and thesolvent was removed using the rotary evaporator. The residue waspurified by flash column chromatography [methylenechloride/methanol/ammonia (90:10:1)]. 0.40 g (0.86 mmol, 33%)(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolwas obtained as a yellowish solid.

[0175] MS: (M+H)=501, (M−H)=499

[0176] R_(f): 0.27 [methylene chloride/methanol/ammonia (90:10:1)]

[0177] b) Enantiomerically Pure Synthesis of(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol

[0178] 0.025 g (0.11 mmol) platinum(IV)oxide were added to a solution of0.15 g (0.28 mmol)(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolin 10 mL tetrahydrofuran/toluene (1:1). The reaction mixture was shakenin an autoclave under a hydrogen pressure of 10 psi at ambienttemperature for 16 h. The hydrogen pressure was released, theplatinum(IV)oxide was filtered off and the filtrate was freed fromsolvent using the rotary evaporator. 0.14 g (0.28 mmol, 99%)(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolwas obtained as a brown oil.

[0179] MS: (M+H)=471, (M−H)=469

[0180] R_(f): 0.26 [ethyl acetate/methanol/ammonia (90:10:1)]

[0181] c)(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamide

[0182] 0.10 mL (41 mmol) benzenesulphonic acid chloride were slowlyadded to a solution of 0.20 g (41 mmol)(R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolin 5 mL pyridine at 0° C. with vigorous stirring. After the addition wascomplete the reaction mixture was stirred for 4 h at 0° C. and thenpoured into 40 mL ice water/ethyl acetate (1:1). The phases wereseparated and the aqueous phase was extracted three times with 20 mLethyl acetate. The combined organic phases were dried over magnesiumsulphate and the solvent was removed using the rotary evaporator. 0.14 g(0.28 mmol, 99%)(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamidewas obtained as a white solid.

[0183] MS: (M+H)=611, (M−H)=609

[0184] R_(f): 0.36 [methylene chloride/methanol/ammonia (90:10:1)]

[0185] d) Enantiomerically Pure Synthesis of(R)N-(5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-2-hydroxy-phenyl)-benzenesulphonamide

[0186] 0.10 g palladium (5% on activated charcoal) were added to asolution of 0.30 g (0.41 mmol)(R)-N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamidein 15 mL ethanol. The reaction mixture was shaken in an autoclave undera hydrogen pressure of 20 psi at ambient temperature for 3 h. Thehydrogen pressure was released, the palladium was filtered off and thefiltrate was freed from solvent using the rotary evaporator. The residuewas purified by flash column chromatography [methylenechloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%)(R)-1-(4-benzyloxy-3-nitrophenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanolwas obtained as a colourless solid.

[0187] MS: (M+H)=521, (M−H)=519

[0188] R_(f): 0.33 [methylene chloride/methanol/ammonia (90:10:1)]

[0189] e) Synthesis of (R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic Acid(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-amide

[0190] 0.10 g palladium (5% on activated charcoal) were added to asolution of 0.20 g (0.41 mmol)(R)-1,2,3,4-tetrahydro-quinoline-8-sulphonic acid(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)propylamino]-1-hydroxy-ethyl}-phenyl)-amidein 20 mL ethanol. The reaction mixture was shaken in an autoclave undera hydrogen pressure of 20 psi at ambient temperature for 6 h. Thehydrogen pressure was released, the palladium filtered off and thefiltrate was freed from solvent using the rotary evaporator. The residuewas purified by flash column chromatography [methylenechloride/methanol/ammonia (90:10:1)]. 0.20 g (0.31 mmol, 75%)(R)-1,2,3,4-tetrahydro-quinoline-8-sulphonicacid(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-amidewere obtained as a colourless solid.

[0191] MS: (M+H)=576, (M−H)=574

[0192] R_(f): 0.32 [methylene chloride/methanol/ammonia (90:10:1)]

EXAMPLE 12

[0193] a) Racemic Synthesis ofN-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)methanesulphonamide

[0194] 21.1 g (33.0 mmol) ofN-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamideand 7.00 g (30.0 mmol) of1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamine in 150 mL ethanolwere refluxed for 18 h. The reaction mixture was cooled to 0° C. andthen combined with 3 g (77.0 mmol) sodium borohydride. It was stirredfor a further 3 h at ambient temperature and then combined with glacialacetic acid. The solvent was removed using the rotary evaporator and theresidue was dissolved in 300 mL ethyl acetate/water (1:2). The aqueousphase was made alkaline with conc. ammonia and separated from theorganic phase. The organic phase was washed twice with 200 mL water andonce with 200 mL of saturated, aqueous sodium chloride solution, driedover sodium sulphate and freed from solvent using the rotary evaporator.The residue was dissolved in 70 ml warm ethanol, combined with 5.4 g ofoxalic acid and the oxalate formed was recrystallised from ethanol. 16.0g (22.0 mmol, 73%)N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)methanesulphonamidewere obtained as the oxalate.

[0195] Melting point: 183-184° C.

[0196] b) Racemic Synthesis ofN-(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)methanesulphonamide

[0197] The base was liberated from 16.0 g of oxalate ofN-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)methanesulphonamideby known methods. 1.5 g palladium (5% on activated charcoal) were addedto a solution of the free base in 150 mL methanol. The reaction mixturewas shaken in an autoclave under a hydrogen pressure of 20 psi atambient temperature for 6 h. The hydrogen pressure was released, thepalladium filtered off and the filtrate was freed from solvent using therotary evaporator. The residue was recrystallised from acetonitrile. 3.9g (93%) ofN-(5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)methanesulphonamidewere obtained as a colourless solid.

[0198] Melting point: 133-136° C.

EXAMPLE 27

[0199] a) Racemic Synthesis ofN-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodimidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamide

[0200] 2.1 g (7.7 mmol) of3-(4-iodimidazol-1-yl)-1,1-dimethyl-propylamine and 3.4 g (7.7 mmol) ofN-[2-benzyloxy-5-(2-ethoxy-1,2-dihydroxy-ethyl)-phenyl]-phenylsulphonamidein 25 mL ethanol were refluxed for 18 h. The reaction mixture was cooledto 0° C. and then combined with 0.3 g (7.7 mmol) sodium borohydride. Themixture was stirred for a further 3 h at ambient temperature and thencombined with glacial acetic acid. The solvent was removed using therotary evaporator and the residue was dissolved in 300 mL ethylacetate/water (1:2). The aqueous phase was made alkaline with conc.ammonia and separated from the organic phase. The organic phase waswashed twice with 100 mL water and once with 100 mL of saturated aqueoussodium chloride solution, dried over sodium sulphate and freed fromsolvent using the rotary evaporator. The residue was purified by flashcolumn chromatography [methylene chloride/methanol/ammonia (90:10:1)].3.5 g (5.0 mmol, 69%)N-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamidewere obtained as a yellowish solid.

[0201] MS: (M+H)=661, (M−H)=659

[0202] R_(f): 0.51 [methylene chloride/methanol/ammonia (90:10:1)]

[0203] b) Racemic Synthesis ofN-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-phenyl)-phenylsulphonamide

[0204] 0.500 g (0.757 mmol) ofN-(2-benzyloxy-5-{1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl}-phenyl)-phenylsulphonamide,0.211 g (1.51 mmol) of 4-fluoro-phenylboric acid, 0.012 g (0.010 mmol)of tetrakis(triphenylphosphino)palladium and 0.010 g (0.010 mmol) oftetrabutylammonium bromide in 20 mL saturated, aqueous sodium hydrogencarbonate solution/toluene (1:1) were refluxed for 3 d. The reactionmixture was combined with 100 mL toluene water (1:1) at ambienttemperature, the phases were separated and the organic phase was washedthree times with 50 mL water. The organic phase was dried over sodiumsulphate and freed from solvent using the rotary evaporator. The residuewas purified by flash column chromatography [methylene chloride/methanol(90:10)]. 0.420 g (0.668 mmol, 88%)N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenyl-imidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-phenylsulphonamidewere obtained as a colourless oil.

[0205] MS: (M+H)=629, (M−H)=627

[0206] R_(f): 0.36 [methylene chloride/methanol (90:10)]

EXAMPLE 25

[0207] a) Racemic Synthesis of1-(4-benzyloxy-2-fluoro-phenyl)-2-[3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethanol

[0208] 12.2 g (40.0 mmol) of1-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-2-hydroxy-ethanone and 9.2 g(30.0 mmol) 3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamine in200 mL ethanol were refluxed for 18 h. The reaction mixture was cooledto 0° C. and then combined with 3 g (77.0 mmol) of sodium borohydride.The mixture was stirred for a further 3 h at ambient temperature andthen combined with glacial acetic acid. The solvent was removed usingthe rotary evaporator and the residue was dissolved in 300 mL ethylacetate/water (1:2). The aqueous phase was made alkaline with conc.ammonia and separated from the organic phase. The organic phase waswashed twice with 200 mL water and once with 200 mL saturated, aqueoussodium chloride solution, dried over sodium sulphate and freed fromsolvent using the rotary evaporator. The residue was dissolved in 70 mlwarm ethanol, combined with 3.5 g of fumaric acid and the fumarateobtained was recrystallised from ethanol. 11.0 g (20.0 mmol, 50%)1-(4-benzyloxy-2-fluoro-phenyl)-2-[3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethanolwere obtained as the fumarate.

[0209] Melting point: 182-183° C.

[0210] b) Racemic Synthesis of4-{2-[3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-3-fluoro-phenol

[0211] The base was liberated from 7.0 g of fumarate of1-(4-benzyloxy-2-fluoro-phenyl)-2-[3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethanolby known methods. 1.0 g palladium (5% on activated charcoal) were addedto a solution of the free base in 100 mL methanol. The reaction mixturewas shaken in an autoclave under a hydrogen pressure of 20 psi atambient temperature for 6 h. The hydrogen pressure was released, thepalladium was filtered off and the filtrate was freed from solvent usingthe rotary evaporator. The residue was recrystallised from acetonitrile.3.9 g (93%)4-{2-[3-(4,5-diphenyl-imidazol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-3-fluoro-phenolwere obtained as a colourless solid.

[0212] Melting point: 163-165° C.

[0213] The compounds of formulae (IA), (IB) and (IC) listed in Tables 1,2 and 3 are obtained, inter alia, analogously to the procedure describedhereinbefore. The abbreviations X₁, X₂, X₄, X₅, X₆, X₈ and X₁₂ used inthe Tables in each case denote a link to a position in the generalformula shown under Table 1 instead of the corresponding groups R¹, R²,R⁴, R⁵, R⁶, R⁸ and R¹². TABLE 1 (IA)

stereo- chemis- Ex. R1 R2 R4 R5 R6 R8 R12 try* 1

H

H H R 2

H

H H R 3

H

H H R 4

H

H H R 5

H

H₃C—X₅

H H R 6

H

H H R 7

H

H H R 8

H H H

H R 9

H H H

H H R 10

H H H

H H R 11

H H

H H R 12

H

H H rac 13

H

H H R 14

H

H

R 15

H

H H R 16

H

H

R 17

H

H

R 18

H

H

R 19

H

H H R 20

H

H

S 21

H

H H S 22

H

H H S 23

H

H H S 24

H

H H rac 25 H F

H H rac 26 H F

H H rac 27

H

H

rac 28

H

H H rac

[0214] TABLE 2 (IB)

molecular weight determined Example R1 by mass spectrometry 29

589 30

555 31

604 32

589 33

605 34

573 35

597 36

625 37

599 38

599 39

563 40

539 41

535 42

547 43

525 44

473 45

501 46

589 47

539 48

539 49

605 50

589 51

555 52

614 53

527 54

662 55

566 56

647 57

563 58

536 59

539 60

555 61

578 62

566 63

551 64

577 65

539 66

535 67

485 68

601 69

527 70

528 71

514 72

516 73

528 74

536 75

534

[0215] TABLE 3 (IC)

molecular weight determined by Example R1 mass spectrometry 76

566 77

571 78

555 79

535 80

535 81

657 82

589 83

597 84

613 85

567 86

535 87

565 88

527 89

527 90

555 91

549 92

561 93

539 94

571 95

589 96

539 97

511 98

557 99

549 100

565 101

605 102

577 103

577 104

557 105

546 106

557 107

605 108

578 109

536

[0216] As has been found, the compounds of general formula (I) arecharacterised by their great versatility in the therapeutic field.Particular mention should be made of those applications in which theeffects of beta-3-agonists, particularly selective beta-3-agonists playa part.

[0217] Such diseases include for example:

[0218] atherosclerosis, cholangitis, gall bladder disease, chroniccystitis, chronic bladder inflammation; chronic prostatitis, cystospaz,depression, duodenal ulcer, duodenitis, dysmenorrhoea; increasedintraocular pressure and glaucoma, enteritis, oesophagitis, gastriculcer, gastritis, gastrointestinal disorders caused by contraction(s) ofthe smooth muscle, gastrointestinal disorders incl. gastric ulcer;gastrointestinal ulceration, gastrointestinal ulcers, glaucoma,glucosuria , hyperanakinesia, hypercholesterolaemia, hyperglycaemia,hyperlipaemia, arterial hypertension, hypertriglyceridaemia, insulinresistance, intestinal ulceration or small bowel ulcers (incl.inflammatory bowel diseases, ulcerative colitis, Crohn's disease andproctitis=inflammation of the rectum), irritable colon and otherdiseases with decreased intestinal motility, depression, melancholy,pollacisuria, frequent urinary urgency, nervous neurogenic inflammation,neurogenic bladder dysfunction, neurogenic inflammation of therespiratory tract, neuropathic bladder dysfunction, nycturia,non-specific diarrhoea, dumping syndrome, obesity, fatness,pancreatitis, inflammation of the pancreas, stomach ulcers, prostatediseases such as benign prostatic hyperplasia, enlarged prostate, spasm,cramp, type 2 diabetes mellitus, irritable bladder or concrement of thelower urinary tract.

[0219] The beta-3 agonists according to the invention are particularlysuitable for the treatment of obesity, insulin resistance; type 2diabetes mellitus; urinary incontinence; irritable colon and otherdiseases with decreased intestinal motility or depression, particularlyfor the treatment of diabetes and obesity. The activity of the beta-3agonists can be determined for example in a lipolysis test. The testprocedure may be carried out as follows:

[0220] Adipocytes were isolated from fatty tissue ex vivo by modifying amethod according to Rodbell (Rodbell, M. Metabolism of isolated fatcells. I. Effects of hormones on glucose metabolism and lipolysis. JBiol Chem 239: 375-380. 1964). The excised fatty tissue was cut intosmall pieces and mixed with 1 mg/ml collagenase in Krebs Ringer Buffer(KRB) containing 6 mM glucose and 2% albumin by gently shaking for 30-40min at 37° C. The cells were filtered through a gauze, washed twice withKRB and in each case 50-150 g were centrifuged for 5 min. 10 μl of thecentrifuged adipocytes were incubated with 90 μl of a compound accordingto the invention (agonist) at concentrations of between 10⁻¹⁵ to 10⁻⁴ M.The agonists were incubated over 40 min at 37° C. A varying release ofglycerol in the medium indicated that the fat cell lipolysis had alteredas a result of the addition of the agonist. Released glycerol wasdetected enzymatically with a Sigma kit (triglyceride (GPO Trinder)Reagent A; Cat. # 337-40A), as described below.

[0221] Glycerol is phosphorylated by ATP via glycerol kinase. Theresulting glycerol-1-phosphate is oxidised by glycerolphosphate oxidaseto form dihydroxyacetone phosphate and hydrogen peroxide. Then aquinonimine dye is produced by the peroxidase-catalysed coupling ofsodium-N-ethyl-N-(3-sulphopropyl)m-ansidine and 4-aminoantipyrine. Thedye has an absorption peak at 540 nm. The absorption is directlyproportional to the glycerol concentration in the samples.

[0222] The new compounds may be used for the prevention or short-term orlong-term treatment of the above-mentioned diseases, and may also beused in conjunction with other active substances used for the sameindications. These include, for example, antidiabetics, such asmetformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride),nateglinide, repaglinide, thiazolidine-dione (e.g. rosiglitazone,pioglitazone), PPAR-gamma agonists (e.g. GI 262570), alpha-glucosidaseinhibitors (e.g. acarbose, voglibose), alpha2 antagonists, insulin andinsulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.Also, inhibitors of protein tyrosine phosphatase 1, substances whichinfluence deregulated glucose production in the liver, such as e.g.inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase,glycogen phosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, lipid lowering agents, such as HMG-CoA-reductaseinhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate,fenofibrate), nicotinic acid and its derivatives, cholesterol absorptioninhibitors such as for example ezetimibe, bile acid-binding substancessuch as for example cholestyramine, HDL-raising compounds such as forexample inhibitors of CETP or regulators of ABC1 or active substancesfor the treatment of obesity, such as e.g. sibutramine ortetrahydrolipostatin.

[0223] In particular, they may also be combined with drugs for treatinghigh blood pressure such as e.g. All antagonists or ACE inhibitors,diuretics, β-blockers, and other modulators of the adrenergic system orcombinations thereof. In addition, combinations with stimulators of theadrenergic system via alpha 1 and alpha 2 and also beta 1, beta 2 andbeta 3 receptors are particularly suitable.

[0224] The compounds of general formula (I) may be used on their own orin conjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions,—particularly solutions for injection (s.c.,i.v., i.m.) and infusion—elixirs, emulsions or dispersible powders. Thecontent of the pharmaceutically active compound(s) should be in therange from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of thecomposition as a whole, i.e. in amounts which are sufficient to achievethe dosage range specified below. The specified doses may be takenseveral times a day, if necessary.

[0225] Suitable tablets may be obtained, for example, by mixing theactive substance(s) with known excipients, for example inert diluentssuch as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as corn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

[0226] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example collidone or shellac, gum arabic, talc,titanium dioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0227] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharine, cyclamate, glycerol or sugar and aflavour enhancer, e.g. a flavouring such as vanilline or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0228] Solutions for injection and infusion are prepared in the usualway, e.g. with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,optionally organic solvents may optionally be used as solvating agentsor dissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

[0229] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0230] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof.

[0231] Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

[0232] The preparations are administered by the usual methods,preferably by oral or transdermal route, preferably oral. For oraladministration the tablets may, of course contain, apart from theabove-mentioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

[0233] For parenteral use, solutions of the active substances withsuitable liquid carriers may be used.

[0234] The dosage for intravenous use is from 1-1000 mg per hour,preferably between 5 and 500 mg per hour.

[0235] However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

[0236] The formulation Examples which follow illustrate the presentinvention without restricting its scope:

EXAMPLES OF PHARMACEUTICAL FORMULATIONS

[0237] A) Tablets per tablet active substance 100 mg lactose 140 mg cornstarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

[0238] The finely ground active substance, lactose and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B) Tablets per tablet activesubstance  80 mg lactose  55 mg corn starch 190 mg microcrystallinecellulose  35 mg polyvinylpyrrolidone  15 mg sodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg

[0239] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C) Ampoule solution active substance 50 mg sodium chloride 50 mgwater for inj.  5 ml

[0240] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mgand 50 mg of active substance.

1. Compounds of general formula (I),

wherein R¹, R², R¹⁰, R¹¹ independently of one another denote a groupselected from among hydrogen, halogen, CN, NO₂, and —NHCXNH₂ or a groupselected from among optionally substituted —COR⁷, —COOR⁷, —CONR⁷R¹³,—OR¹⁴, NR¹³R¹⁵, C₁-C₁₀-alkyl, C₃-C₈-cycloalkyl, —NR¹⁶CX—R¹⁷,—NR¹⁸CX—OR¹⁹, —NR²⁰SO_(m)R²¹, —SO_(p)NR²²R²³and —SO_(q)R²⁴. m, p, qdenotes 0, 1 or 2 n denotes 0, 1, 2 or 3 R³ denotes hydrogen or a groupselected from among optionally substituted C₁-C₁₀-alkyl, C₆-C₁₀-aryl,heterocyclyl and C₃-C₈-Cycloalkyl, —CX—C₁-C₁₀-alkyl, —CX—C₆-C₁₄-aryl,R⁴, R⁵ independently of one another denote hydrogen, halogen oroptionally substituted C₁-C₁₀-alkyl, or R⁴ and R⁵ together denote aC₃-C₈-alkyl bridge, R⁶ denotes a group selected from among the generalformulae

l,k independently of one another denote 1, 2 or 3, R²⁵, R²⁶, R²⁷, R²⁸independently of one another denote a group selected from amonghydrogen, OH, halogen, CN and NO₂, or a group selected from amongoptionally substituted C₁-C₁₀-alkyl, C₆-C₁₈-aryl, heteroaryl,heterocyclyl, —CX—R¹⁷, —OR¹⁴, NR¹³R¹⁵, C₂-C₈-cycloalkyl —NR²⁰SO_(m)R²¹,—SO_(p)NR²²R²³, —SO_(q)R²⁴, —NR¹⁸CX—R¹⁹, —NR¹⁸CXOR¹⁷,while R²⁵ and R²⁶cannot simultaneously denote hydrogen, R⁸ denotes hydrogen or a groupselected from among optionally substituted C₁-C₁₀-alkyl, C₆-C₁₈-aryl,—SO_(q)—C₁-C₁₀-alkyl, —SO_(q)—C₆-C₁₄-aryl, —CX—C₁-C₁₀-alkyl,—CX—C₆-C₁₄-aryl, C₆-C₁₀-aryl, heterocyclyl and C₃-C₈-cycloalkyl R⁹denotes hydrogen or a group selected from among optionally substitutedC₁-C₁₀-alkyl, C₆-C₁₄-aryl, heteroaryl, C₃-C₈-cycloalkyl andheterocycloalkyl, R¹² denotes hydrogen or a group selected from amongoptionally substituted benzyl, C₁-C₁₂-alkyl and C₆-C₁₄-aryl, R⁷, R¹³,R¹⁵, R¹⁶, R¹⁸, R²⁰, R²², R²³ independently of one another denotehydrogen, or a group selected from among optionally substitutedC₁-C₁₀-alkyl, C₆-C₁₄-aryl, heterocyclyl and C₃-C₈-cycloalkyl R¹⁴, R¹⁹,R²⁹ independently of one another denote hydrogen or a group selectedfrom among optionally substituted C₁-C₁₀-alkyl, C₆-C₁₄-aryl,C₃-C₈-cycloalkyl, heteroaryl, heterocyclyl, —CXNR₁₃R₁₅ and —CXR₇ R¹⁷denotes a group selected from among C₁-C₁₀-alkyl, C₆-C₁₄-aryl,heterocyclyl, heteroaryl and C₃-C₈-cycloalkyl R²¹, R²⁴ independentlydenote hydrogen or OH, or a group selected from among optionallysubstituted N(C₁-C₁₀-alkyl)₂, N(C₃-C₈-cycloalkyl), C₁-C₁₀-alkyl,C₆-C₁₄-aryl, heterocyclyl, heteroaryl and C₃-C₈-cycloalkyl and X denotesO, S or NR²⁹, optionally in the form of the tautomers, the racemates,the enantiomers, the diastereomers and the mixtures thereof, as well asoptionally the pharmacologically acceptable acid addition salts thereof.2. Compounds according to claim 1, wherein R¹⁰, R¹¹ independently of oneanother denote hydrogen or halogen, m, p, q independently of one anotherdenote 0, 1 or 2 n denotes 0, 1, 2 or 3 R³ denotes hydrogen orC₁-C₅-alkyl R⁴, R⁵ independently of one another denote hydrogen orC₁-C₅-alkyl, R⁸ denotes a group selected from among hydrogen,C₁-C₅-alkyl, —SO_(q)—C₁-C₅-alkyl, —SO_(q)—C₆-C₁₄-aryl, phenyl andC₃-C₆-cycloalkyl R⁹ denotes hydrogen or C₁-C₁₀-alkyl R¹² denoteshydrogen or benzyl R¹³, R¹⁵, R¹⁶, R¹⁸ independently of one anotherdenote a group selected from among hydrogen, C₁-C₅-alkyl,C₃-C₆-cycloalkyl and phenyl R¹⁴, R¹⁹ independently of one another denotehydrogen or C₁-C₅-alkyl, and R¹⁷ denotes optionally substitutedC₁-C₅-alkyl or C₆-C₁₀-aryl.
 3. Compounds according to claim 1 or 2,wherein R^(10,) R¹¹ denote hydrogen m, p, q denote 0, 1 or 2 n denotes0, 1, 2 or 3 R³ denotes hydrogen R⁴, R⁵ independently of one anotherdenote hydrogen or methyl, R⁸ denotes hydrogen, —SO_(q)—C₆-C₁₄-aryl or—SO₂—C₁-C₅-alkyl R⁹ denotes hydrogen R¹² denotes hydrogen or benzyl,R¹³, R¹⁵, R¹⁶, R¹⁸ independently of one another denote a group selectedfrom among hydrogen, C₁-C₁₅-alkyl and phenyl, R¹⁴, R¹⁹ independently ofone another denote hydrogen or C₁-C₅-alkyl, and R¹⁷ denotes C₁-C₅-alkylor C₆-C₁₄-aryl.
 4. Compounds according to one of claims 1 to 3, whereinR¹ denotes a group selected from among hydrogen, NO₂, NH₂, —NHCX—R¹⁷ and—NHSO₂R²¹ R² denotes hydrogen or halogen n denotes 2, R³ denoteshydrogen R⁴, R⁵ denote hydrogen or methyl R⁶ denotes a group selectedfrom among the general formulae

l,k denote 1 R²⁶, R²⁷ denote hydrogen, R⁸ denotes hydrogen or —SO₂CH₃,R⁹ denotes hydrogen, R^(10,) R¹¹ denote hydrogen, and R¹² denoteshydrogen or benzyl.
 5. Compounds according to one of claims 1 to 4,wherein R⁶ denotes a group selected from among the general formulae


6. Compounds according to one of claims 1 to 5, wherein R⁶ denotes anoptionally substituted group of formula (j)


7. Compounds of formula (I) according to one of claims 1 to 6 for use aspharmaceutical compositions.
 8. Compounds of formula (I) according toone of claims 1 to 6 for use as pharmaceutical compositions with aselective beta-3-agonistic activity.
 9. Use of a compound of formula (I)according to one of claims 1 to 6 for preparing a pharmaceuticalcomposition for the treatment and/or prevention of diseases connectedwith the stimulation of beta-3-receptors.
 10. Method for the treatmentand/or prevention of diseases connected with the stimulation ofbeta-3-receptors, characterised in that an effective amount of acompound of formula I according to claim 1 to 6 is administered to apatient.
 11. Pharmaceutical composition, containing as active substanceone or more compounds of general formula (I) according to one of claims1 to 6 or the physiologically acceptable salts thereof optionallycombined with conventional excipients and/or carriers. 12.Pharmaceutical composition containing as active substance one or morecompounds of general formula (I) according to one of claims 1 to 6 orthe physiologically acceptable salts thereof and one or more activesubstances selected from among antidiabetics, inhibitors of proteintyrosinephosphatase 1, substances which influence deregulated glucoseproduction in the liver, lipid lowering agents, cholesterol absorptioninhibitors, HDL-raising compounds, active substances for the treatmentof obesity and modulators or stimulators of the adrenergic via alpha 1and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.
 13. Processfor preparing a compound of general formula (I),

wherein R¹-R²⁸ and X may have the meanings given in claims 1 to 6,characterised in that a compound of general formula (II)

wherein R⁴ and R⁵ have the meanings given in claims 1 to 6, is convertedby means of a chlorinating agent into a compound of formula (III)

the compound of formula (III), optionally provided with an aminoprotective group, is reacted with an optionally substituted compoundselected from among the general formulae (IVa) to (IVi)

wherein k, l, R²⁷ and R²⁸ have the meanings given in claims 1 to 6, andthe product of formula (V)

wherein n, R⁴, R⁵, R⁶ and R⁸ have the meanings given in claims 1 to 6,is reacted with a compound of formula (VI)

wherein R¹, R², R⁹ and R¹⁰ to R ¹² have the meanings given in claims 1to 6.